1. Field of the Invention
The present invention relates to reducing or preventing impairment of respiratory tract mucosal immunity and risk of pneumonia associated with a lack of enteral feeding, such as with the use of total parenteral nutrition (TPN) or, more generally, with a lack of immunological stimulation of the gastrointestinal tract through oral or gastrointestinal feeding. In particular, the present invention relates to methods of reducing or preventing impairment of respiratory tract mucosal immunity. The present invention also relates to compositions useful in such methods.
2. Description of the Related Art
Infectious complications are the most common cause of death following trauma in patients without head injuries (Baker et al., Am J Surg., 140:144-150 (1980)), and a frequent cause of morbidity and mortality in malnourished patients, patients sustaining surgical complications, and patients requiring prolonged intensive care unit (ICU) stays. Despite intravenous (IV) nutrition, multiple antibiotics, and aggressive ICU care, mortality from sepsis (i.e., the presence of pathogenic organisms or their toxins in the blood or tissues) averages 30%, with a range of 20-60% depending upon the patient population studied (Bone et al., Crit. Care Med., 17:389-393 (1989); Bone et al., N. Eng. J. Med., 317:653-658 (1987); Ziegler et al., N. Eng. J. Med., 324:429-436 (1991); Hinshaw et al., N. Eng. J. Med., 317:659-665 (1987); and Kreger et al., Am. J. Med., 68:344-34 (1980)). Septic morbidity, especially pneumonia, is significantly reduced in critically injured patients when enteral feeding rather than parenteral feeding or no feeding at all is provided (Kudsk et al., Ann. Surg., 224:531-543 (1996). This suggests that enteral feeding provides benefits to host defenses (Kudsk et al., Ann. Surg., 215:503-513 (1992); Moore et al., J. Trauma, 26:874-881 (1986); Moore et al., J. Trauma, 29:916-923 (1989); and Moore et al., Ann. Surg., 216:172-183 (1992)).
The mechanisms responsible for improved recovery with the use of enteral feeding are poorly understood, but it is hypothesized that lack of enteral feeding leads to a breakdown in the gastrointestinal barrier, thus allowing molecules and perhaps bacteria to gain entry into the body resulting in inflammation and distant infection (Deitch, J. Trauma, 30:S184-S189 (1990); Deitch, Surgery, 107:411-416 (1990); Ziegler et al., Arch. Surg., 123:1313-1319 (1988); Deitch et al., Ann. Surg., 205:681 (1987); and Deitch, Perspect. Crit. Care, 1:1-31 (1988)). Most investigators have studied barrier integrity by focusing on changes in gut morphology and permeability to bacteria and macromolecules (Bushman et al., Gastroenterology, 104:A612 (1993)).
Nutritional models which preserve IgA (i.e., immunoglobulin A) within the mucin layer also appear to preserve normal gastrointestinal (GI) colonization and reduce bacterial translocation (Deitch et al., JPEN, 17:332-336 (1993); and Haskel et al., Ann. Surg., 217:634-643 (1993)). Although systemic responses to injury increase gut permeability in some patients, data demonstrating that this increased permeability causes infectious complications, such as pneumonia, are not convincing (Deitch, Surgery, 107:411-416 (1990); Ziegler et al., Arch. Surg., 123:1313-1319 (1988); and Langkamp-Henken et al., Crit. Care Med., 23:660-664 (1995)).
Components in mucosal defense and barrier integrity up-regulated by bombesin include lactoferrin, peroxidases, lysozymes, the mucin, and high molecular weight glycoprotein. IgA is one of the primary immunologic defenses against many mucosal infections. Moreover, a critical component in mucosal defense and barrier integrity is the availability of secretory IgA (sIgA) in the mucin layer coating the mucosa (Svanborg et al. in Ogra et al., eds., Handbook of Mucosal Immunology, 71-78; and Killian et al. in Ogra et al., eds., Handbook of Mucosal Immunology, 127-140). sIgA binds or agglutinates bacteria, viruses, and potentially other toxic molecules, eliminating the key to invasive mucosal infection, i.e., adherence of infectious agents to human mucosal cells (Svanborg in Ogra et al., eds., Handbook of Mucosal Immunology, 71-78). Levels of IgA are dependent upon adequate numbers of functioning immunocompetent cells in the lamina propria and a cytokine milieu appropriate to the production of IgA (Kiyono et al. in Ogra et al., eds., Handbook of Mucosal Immunology, 263-274; and Lebman et al. in Ogra et al., eds., Handbook of Mucosal Immunology, 243-250). As IgA is released from plasma cells within the lamina propria, it is transported through mucosal epithelia cells by secretory components. In the mucin layer, sIgA binds and agglutinates potential noxious agents without inducing inflammation. sIgA also appears to improve the functional capabilities of other immune cells such as, neutrophils, to mount defenses against infectious agents.
Once initial activation of precursor IgA-producing cells occurs within the Peyer""s patches, the antigen-sensitized cells undergo mitotic changes and the resulting B lymphoblasts migrate to regional lymph nodes and eventually to the systemic circulation via the thoracic duct (Tomasi, Jr., Rev. Infect. Dis., 5:S784-S792 (1983)). Experiments using whole bacteria, bacterial products, live or killed viruses, or modified viral antigens have shown that the antigen-sensitized precursor cells home not only to the GI tract but also to the respiratory tract, and mammary, parotid, and lacrimal glands where they produce IgA for transport through the epithelial cells into external secretions if the appropriate T cell signals and antigenic stimulation exist (Kiyono et al. in Ogra et al., eds., Handbook of Mucosal Immunology, 263-274; Mestecky et al. in Ogra et al., eds., Handbook of Mucosal Immunology, 357-372; Mestecky, J., J. Clin. Immunol., 7:265-276 (1987); and McGhee et al., Vaccine, 10:75-88 (1992)).
These observations have led to the concept of a common mucosal immune system and explain the extra-intestinal effects of enteral or parenteral feeding on respiratory tract immunity. The concept of a common mucosal immune system may be the link between intestinal changes and extra-intestinal susceptibility to infection, in particular the respiratory tract.
The human body devotes significant resources to maintain mucosal immunity, including 50% of its functioning immune cells to produce secretory IgA to help control its endogenous microbial GI flora (Brandtzaeg in Ogra et al., eds., Handbook of Mucosal Immunology, 3-8; Tomasi in Ogra et al., eds., Handbook of Mucosal Immunology, 251-262). The mucosal immune circuit initially begins with antigenic uptake via M cells, which are the cells overlying the intestinal lymphatic follicle of the Peyer""s patches (PP). B cells (i.e., B lymphocytes), sensitized by antigen processed within the Peyer""s patches, then migrate to the mesenteric lymph nodes where, under the appropriate cytokine milieu, they proliferate and migrate via the thoracic duct into the vascular tree. Once in the vascular system, these sensitized cells home to the lamina propria of the intestine, producing IgA which plays an important role in gut barrier function (Ottaway, Gastro. Clin. North Am., 20:511-529 (1991); and Salmi et al., Gastroenterol. Clin. North Am, 20:495-505 (1991)).
Specialized enteral nutritional support has been used to reduce malnutrition and the incidence of infectious complications in critically ill persons. Certain patients, however, are often unable to tolerate enteral feedings and must be fed parenterally. Lack of enteral feeding or a lack of immunological stimulation of the GI tract, such as may occur with intravenous TPN, for example, can lead to atrophy of the small intestinal gut-associated lymphoid tissue (GALT); decreases in intestinal and respiratory tract IgA levels; as well as increases in mucosal permeability, bacterial overgrowth, and bacterial translocation. Lack of enteral feeding or a lack of immunological stimulation of the gastrointestinal tract also impairs established respiratory tract mucosal immunity to an IgA-mediated infectious viral agent and to bacteria which generate specific IgA responses such as Pseudomonas aeruginosa. This is consistent with the results of experiments which show that the route and type of nutrition affects levels of IgA, bacterial flora changes, and mucosal permeability. With few exceptions, bacterial overgrowth, mucosal permeability, and increased translocation of both bacteria and macromolecules have shown an inverse correlation with intestinal IgA levels.
Neuropeptides are hormones released by nerve fibers within the intestinal wall. Bombesin (BBS), a tetradeca-neuropeptide analogous to mammalian gastrin-releasing peptide, stimulates the release of gastrointestinal hormones, increases levels of intestinal sIgA (Debas et al., Am. Surg., 161:243-249 (1991)), reduces bacterial translocation (Haskel et al., Ann. Surg., 217:634-643 (1993)), and improves mortality in a lethal enterocolitis model (Chu-Ku et al., Ann. Surg., 220:570-577 (1994)). Additionally, bombesin may up-regulate specific cellular immunity, either directly or acting through other hormones released in response to its administration (Jin et al., Dig. Dis. Sci., 34:1708-1712 (1989)).
Bombesin, originally isolated from frog skin, is structurally related to mammalian gastrin-releasing neuropeptide (Spindel, Trends Neurosci., 9:130-133 (1986)). This neuropeptide stimulates gastric and pancreatic secretion, alters gastrointestinal motility, and elicits the release of a variety of gastrointestinal hormones, including gastrin, somatostatin, cholecystokinin, pancreatic polyneuropeptide, insulin, glucagon, and neurotensin (Pascual et al. in Ogra et al., eds., Handbook of Mucosal Immunology, 203-216; and Debas et al., Am. J. Surg., 161:243-249 (1991)).
In experiments using IV administration of bombesin to stimulate human natural killer cell activity against human K-562 tumor cells (Van Tol et al., J. Neuroimmunol., 42:139-145 (1993)), in vivo bombesin infusion produced a greater antitumor response than in vitro bombesin incubation, suggesting that mediators other than bombesin may be involved in the increased mobilization of active NK cells into the blood stream. In addition, peripheral blood lymphocytes contain receptors for neurotensin, a neuropeptide released in response to bombesin administration (Evers et al., Surgery, 116:134-140 (1994)).
Bombesin has been mainly studied for its satiety effect in humans (Gibbs et al., Ann. N. Y. Acad. Sci., 547:210-216 (1998); Hilderbrand et al., Regulatory Neuropeptides, 36:423-433 (1991); Muurahainen et al., Am. J. Physiol., 264:R350-R354 (1993); Flynn, Ann. N.Y. Acad. Sci., 739:120-134 (1994); and Lee et al., Neurosci. Biobehav. Rev., 18:313-323 (1994)). However, binding sites for gastrin-releasing neuropeptide have been documented in human bronchi from specimens obtained from patients undergoing thoracotomy for carcinoma (Baraniuk et al., Neuropeptides, 21:81-84 (1992)), and bombesin, as well as other neuropeptides, has been found in the respiratory epithelium of the nasal passages (Hauser-Kronberger et al., Acta. Otolaryngol., 113:387-393 (1993); Gawin et al., Am. J. Physiol., 264:L345-L350 (1993)). Moreover, exogenous administration of bombesin stimulates both in vivo and in vitro human nasal mucus and serous cell secretions, thus increasing total protein, lysozyme, and glycoconjugate secretion, and, thereby, acting as a secretagogue in the upper respiratory tract passages (Baraniuk et al., Am. J. Physiol., 262:L48-L52 (1992)). No increase in albumin secretion accompanies this increased secretion, suggesting that bombesin does not exert its effects through vasodilatation, increases in vascular permeability, or increases in plasma transit across the epithelium.
There is a need in the art for methods and compositions for reducing or preventing impairment of respiratory tract mucosal immunity associated with a lack of enteral feeding, such as total parenteral nutrition (TPN) or fasting. There is also a need in the art for methods and compositions for reducing the rate of respiratory infection by pathogenic microorganisms associated with a lack of enteral feeding or lack of immunological stimulation of the GI tract. Finally, there is a need in the art for methods and compositions for reducing the atrophy or dysfunction of the GALT of an animal associated with a lack of enteral feeding or lack of immunological stimulation of the GI tract. The present invention answers these needs.
The present invention is directed to methods for reducing the impairment of respiratory tract mucosal immunity and, in particular, upper respiratory tract mucosal immunity, associated with a lack of enteral feeding or a lack of immunological stimulation of the GI tract. Methods of the invention administer a therapeutically effective amount of a neuropeptide selected from the group consisting of bombesin, gastrin-releasing polypeptide, a neuropeptide having an amino acid C terminus corresponding to Trp-Ala-Val-Gly-His-Leu-Met-NH2 [SEQ ID NO:1], or mixtures thereof In addition, the methods of the invention administer a therapeutically effective amount of a compound which stimulates the release of one or more of those neuropeptides. The methods of the invention also administer a therapeutically effective amount of a compound which is released in response to such neuropeptides.
The present invention is also directed to methods of reducing the rate of infection by a pathogenic microorganism in an animal associated with a lack of enteral feeding or a lack of immunological stimulation of the gastrointestinal tract. The methods administer a therapeutically effective amount of a neuropeptide selected from the group consisting of bombesin, gastrin-releasing polypeptide, a neuropeptide having an amino acid C terminus corresponding to Trp-Ala-Val-Gly-His-Leu-Met-NH2 [SEQ ID NO:1], or mixtures thereof. The methods also administer a therapeutically effective amount of a compound which stimulates the release of one or more of those neuropeptides. The methods also administer a therapeutically effective amount of a compound which is released in response to such neuropeptides.
Moreover, the present invention is also directed to methods of reducing the atrophy or dysfunction of the small intestinal gut-associated lymphoid tissue (GALT) and generalized mucosal immunity of an animal associated with a lack of enteral feeding or a lack of immunological stimulation of the gastrointestinal tract. In the embodiment, the methods administer to the animal a therapeutically effective amount of a neuropeptide selected from the group consisting of bombesin, gastrin-releasing polypeptide, a neuropeptide having an amino acid C terminus corresponding to Trp-Ala-Val-Gly-His-Leu-Met-NH2 [SEQ ID NO:1], or mixtures thereof. The methods also administer a therapeutically effective amount of a compound which stimulates the release of one or more of those neuropeptides. In addition, the methods administer a compound which is released in response to a neuropeptide, such as those listed above.
In addition, the present invention is directed to compositions useful in reducing impairment of respiratory tract mucosal immunity and, in particular, upper and lower respiratory tract mucosal immunity. Such compositions may contain a therapeutically effective amount of a neuropeptide and, optionally, a pharmaceutically acceptable carrier, wherein the neuropeptide is selected from the group consisting of bombesin, gastrin-releasing polypeptide, a neuropeptide having an amino acid C terminus corresponding to Trp-Ala-Val-Gly-His-Leu-Met-NH2 [SEQ ID NO:1], or mixtures thereof. In another embodiment of the invention, the compositions may contain a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound which stimulates the release of such neuropeptides. In still another embodiment of the invention, the compositions may contain a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound which is released in response to a neuropeptide such as bombesin, gastrin-releasing polypeptide, a neuropeptide having an amino acid C terminus corresponding to Trp-Ala-Val-Gly-His-Leu-Met-NH2 [SEQ ID NO:1], or mixtures thereof.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the invention as claimed. Other objects, advantages and novel features will be readily apparent to those skilled in the art from the following detailed description of the invention.